The invention relates to the local delivery of therapeutic agents, and more particularly, to systems and methods that deliver depots of therapeutic agents into a body of tissue to allow for the treatment of a variety of conditions, including coronary conditions and cardiovascular indications.
Disease, injury and surgery can result in localized tissue damage and morbidity. For example, the principal treatment for occlusive vascular diseases is angioplasty, a procedure in which a balloon is inserted into the vessel and then inflated to dilate the area of narrowing. During inflation, the balloon can damage the vessel wall. It appears that as a result of this damage, in 30 to 50% of cases, the initial increase in lumen dimensions is followed by a localized re-narrowing (restenosis) of the vessel over a time of three to six months. Thus, restenosis can result in the dangerous and localized renarrowing of a patient""s vessel at the site of the recent angioplasty. Like many other localized diseases, restenosis is complex and at present there is no clinically effective treatment for this disease. Gibbons et al., Molecular Therapies for Vascular Diseases, Science vol. 272, pages 617-780 (May 1996).
Restenosis, like many other localized injuries and diseases, has responded poorly to pharmacological therapies and agents. Numerous pharmacological agents have been clinically tested, and none have demonstrated an unequivocal reduction in the incidence of restenosis. However, the failure of these pharmacological therapies may arise from the systemic intolerance of the doses required to achieve local beneficial effects or in the difficulty of providing controlled administration of proper dosages over time. Accordingly, one possible reason for the failure of these therapies is that submaximal doses of pharmacological agents are being administered to avoid the serious side-effects that might result from systemic administration of the proper dosage.
To address this problem, various researchers have proposed methods for site-specific delivery of pharmacologic and molecular therapies. These methods include the direct deposition of therapeutic agents into the arterial wall through an intravascular delivery system, systemic administration of therapeutic agents that have a specific affinity for the injured or diseased tissue, and systemic administration of inactive agents followed by local activation.
At present, systems exist that attempt to achieve localized delivery of therapeutic agents. These systems include dual balloon delivery systems that have proximal and distal balloons that are simultaneously inflated to isolate a treatment space within an arterial lumen. A catheter extends between the two balloons and includes a port that can admit within the treatment space between the balloons an aqueous medium, typically one containing a therapeutic agent. Pressure can be applied to the medium to create conditions conducive to intramural infusion. Other balloon-based localized delivery systems include porous balloon systems, hydrogel-coated balloons and porous balloons that have an interior metallic stent. Other systems include locally placed drug-loaded coated metallic stents and drug-filled polymer stents. Wilensky et al., Methods and Devices for Local Drug Delivery in Coronary and Peripheral Arteries, Trend Cardiovasc Med, vol. 3 (1993).
Although these systems can provide working devices for local drug delivery, the efficacy of these devices turns on, and is limited by, a number of factors including the rate of fluid flux through the vascular wall, the residence time of the deposited agent and the local conditions and vasculature of the deposition site. Essentially, the success of these systems is limited by the amount of time that a delivered drug will stay resident locally before being carried downstream by circulating blood. Further, to the extent that these systems allow the therapeutic agent to be carried away, these systems run the risk of applying a therapeutic agent to areas of the patient""s vasculature where such agents may not be beneficial. Additionally, these existing systems are limited by the amount of drug that can be delivered to the diseased site. Moreover, drug filled polymer stents have structural problems that argue against their use.
Existing systems for local drug delivery, including direct deposition of therapeutic agents through an intravascular delivery system, systemic administration of therapeutic agents that have a specific affinity for the injured or diseased tissue, and systemic administration of inactive agents followed by local activation, all require a functioning vascular system for delivery of the therapeutic agent to the affected tissue. These systems, therefore, are inapplicable in conditions characterized by myocardial ischemia or infarction. When ischemic injury is of sufficient severity and duration, groups of involved cells die and myocardial infarction results. Within the ischemic area, not all cells are equally injured. As ischemia persists, there is wave-like progression of cell death or coagulation necrosis. The prospect for recovery decreases with increasing duration or severity of the ischemic insult. It is difficult to quantitate the extent to which ischemic injury will result in cell necrosis.
Reperfusion can salvage injured tissue even after some cells have become necrotic. However, following reperfusion, cells that have been already injured are particularly vulnerable to further injury. This phenomenon, termed xe2x80x9creperfusion injury,xe2x80x9d paradoxically results in cellular necrosis when circulation returns to a cell population that survived the initial ischemic insult. Many factors contribute to this situation. The endothelium of vessels in the reperfused region have been damaged, causing platelet adherence and leukocyte activation with inflammatory sequelae. Oxygen free radicals are released by damaged cells, causing further cell and organelle damage. The sodium-potassium pump, damaged with the initial ischemia, can lose its regulatory ability and allow free water accumulation during reperfusion, resulting in cell swelling and rupture. Unstable and leaky cell membranes can also lead to calcium accumulation within the cytoplasm with uptake of calcium into mitochondria and formation of insoluble calcium-phosphate crystals. As a consequence, there may be a population of cells killed by the initial ischemic insult, and a further population killed following reperfusion.
Both ischemia and infarction can adversely affect myocardial contractile function. The more extensive the injury, the more severe its impact on ventricular function. Following severe myocardial ischemia, there may be a reversible hypocontractile state called xe2x80x9chibernation,xe2x80x9d a condition of impaired contractility amenable to recovery (the so-called xe2x80x9cstunnedxe2x80x9d myocardium, and frank myocardial infarction, characterized by cell death. Once a population of myocytes becomes necrotic, the injured tissue cannot regenerate itself; mature myocytes lack the capacity for cellular replication. The contribution these necrotic myocytes made to contractile function is, thus irreversibly lost. Restoration of functioning myocardium after frank infarction requires both a restoration of tissue perfusion and a replenishing of viable cells that can assume the contractile role of the infarcted tissues.
In view of the variety of localized cardiovascular conditions affecting human health, it would be advantageous to develop other methods of treatment for patients having localized cardiovascular conditions and in particular to develop methods of treatment that reduce adverse side effects and have heightened efficacy. It would furthermore be advantageous to permit treatment of localized cardiovascular conditions resulting from myocardial ischemia and myocardial infarction through local delivery of therapeutic agents.
It is therefore, an object of the invention to provide methods of treatment of a coronary artery or cardiac indication that provide a longer duration of drug pendency at the site of a localized disease.
It is a further object of the invention to provide systems and methods that reduce or eliminate the downstream flow of a locally delivered agent.
It is a further object of the invention to provide delivery of local therapeutic agents to areas of impaired vascularity.
It is yet a further object of the invention to allow improvement of contractile function in infarcted myocardial tissue.
Other objects of the invention will, in part, be obvious, and, in part, be shown from the following description of the systems and methods shown herein.
To these ends, the invention provides systems and methods for implanting a depot into a tissue wall to thereby deliver a therapeutic agent selected for the condition being treated. In one embodiment, the invention provides systems and methods for delivering a therapeutic agent into the myocardial tissue wall for treating various vascular conditions including restenosis, ischemic tissue, and myocardial infarction. Other applications of the systems and methods described herein include the delivery of angiogenesis compounds that can be implanted into ischemic tissue; and/or antiarrhythmic drugs that can be implanted at the sites of conduction abnormalities. A further application of the systems and methods described herein includes the delivery of cells for implantation into the myocardium, accompanied by angiogenesis compounds that will promote local circulation. Accordingly, the agent being locally delivered can depend on the application at hand, and the term agent, or therapeutic agent, as employed herein will be understood to encompass any agent capable of being locally delivered including, but not limited to, pharmaceutical compositions or formulations, viral or non-viral vectors (e.g., adenovirus vectors, retroviral vectors and the like), implantable (genetically engineered) cells, plasmid-liposome complexes or other DNA delivery complexes, oligonucleotides or any other suitable composition compatible with the subject being treated.
In one embodiment, the invention provides systems and methods for local delivery of at least two therapeutic agents, one of which promotes angiogenesis and the other of which contains cells adapted for implantation into the myocardium. The therapeutic agent that promotes angiogenesis can include any substance that induces the formation of blood vessels, including but not limited to such substances as vascular endothelial growth factor (VEGF), tumor angiogenesis factor (TAF), tumor necrosis factor (TNF), fibroblast growth factor (FGF), wound angiogenesis factor (WAF), other growth factors, and other substances including but not limited to angiogenin, fibrin, prostaglandin E and heparin. Cells adapted for implantation into the myocardium include, but are not limited to, cardiomyocytes and their precursors, skeletal myoblast-derived cells, fibroblasts, genetically modified fibroblasts and bone marrow stromal cells and their derivatives. Cells adapted for implantation into the myocardium can be subjected to genetic manipulation prior to or subsequent to implantation.
In a further embodiment, the invention is understood as an apparatus for delivering therapeutic agents into the myocardium. These apparatus can comprise an outer mechanical element made of a biocompatible material which promotes angiogenesis locally by its contact with the myocardial tissues and further comprising an inner reservoir adapted for delivering cells adapted for implantation in the myocardial tissue. In another embodiment, the inner reservoir contains molecular ligands that possess specific affinity for the cell surface markers on circulating myocyte precursor cells, so that these cells are affixed within the reservoir and subsequently released. In a further embodiment, the biocompatible material of the apparatus comprises a drug releasing compound capable of releasing at least one therapeutic agent. In yet another embodiment, this therapeutic agent is capable of promoting angiogenesis. In a further embodiment, this apparatus is bioresorbable.
The invention can also be understood to include apparatus for delivering at least two therapeutic agents comprising a body formed of a biocompatible material containing at least one reservoir permeable to at least one therapeutic agent. The biocompatible material of the delivery system can include a drug releasing compound capable of releasing at least one therapeutic agent. Therapeutic agents released by the drug releasing compound include, but are not limited to, those capable of promoting angiogenesis. In another embodiment, at least two therapeutic agents are disposed within separate reservoirs, each reservoir permeable to the therapeutic agent within it. In a further embodiment, this apparatus is bioresorbable.
The apparatus can comprise an elongate flexible body having a proximal end and a distal end, a delivery chamber coupled to the distal end of the body and having a space for carrying the therapeutic agent, and a port for releasing the therapeutic agent therefrom. The apparatus can further include an actuator coupled to the distal delivery chamber and being capable of driving therapeutic agent through the port.
The terms proximal and distal as used herein will be understood to describe opposite ends of a device or element, and generally will be employed so that proximal is understood as xe2x80x9caway from the heartxe2x80x9d and distal is understood as xe2x80x9ctowards the heartxe2x80x9d or to mean xe2x80x9ctoward the physicianxe2x80x9d and xe2x80x9caway from the physicianxe2x80x9d respectively.